Syntheses of Quinolizine Derivatives

and Hetero-Ring Substituted Quinolizines 

One of the significant developments in the chemistry of the quinolizines since 1954 was the synthesis of the parent aromatic system, the quinolizinium ion, which was unknown until then. This was achieved by Boekelheide and Gall2 by the condensation of 2-picolyllithium with /3-cthoxypropionaldehyde followed by the steps indicated in the sequence 2 - 3 - 4 - 1. 

This sequence of reactions was later repeated3 with 2,6-lutidyl-lithium to give the corresponding 6-methylquinolizinium ion in improved yield. Several related syntheses based on this pattern were reported by other groups of workers4,5,6 soon after. Richards and Stevens4 reported the formation of 2-ethyl-3-methylquinolizinium 

Aromatization of a tetrahydroquinolizone (5) by means of acetic anhydride and sulfuric acid or acetic anhydride alone leads to the formation of a variety of mono- or di-substituted quinolizinium compounds. Glover and Jones 8 achieved the synthesis of a number of these derivatives starting from 2-cyanopyridine and condensing it with appropriate Grignard reagents followed by cyclization and aromatization as outlined in Eq. (2). An identical method was simultaneously worked out by Nesmeyanov and Rybinskaya9 for the specific synthesis of 2-substituted quinolizinium compounds. This 

Nesmeyanov and M. I. Rybinskaya, Dokl. Akad. Nauk SSSR 116, 93 (1957). 

In this section syntheses producing the ring systems will be described interconversion of functional groups will be found in Section III. 

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In principle, most of the syntheses of quinolizones could be applied to the synthesis of benzoquinolizones by starting with the quinoline or isoquinoline equivalent of the pyridine component. Thus Kappe84 has obtained the hydroxybenzo[ ]quinolizin-4-ones 70, and the hydroxybenzo[c]quino-lizin-l-ones 71 from methylquinolines, quinolyl- or isoquinolylacetates, and malonic esters or carbon suboxide. Kato and co-workers37-38 have used the Vilsmeier derivatives of 2-quinolylacetate with diketene (Eq. 39)37 or with anhydrides (Eq. 40)38 to give benzo[e]quinolizin-l-ones. 

In this section are described the syntheses of some simple indolo-[2,3-a]quinolizine derivatives which bear a close relationship to the alkaloids of the yohimbane and corynane groups. 

Several other groups have made use of the Smith indole synthesis, and a summary of this work is shown in Table 1. Gribble and cowoikers prepared 2-(2-pyridinyl)indoles en route to syntheses of several zwitterionic indolo[2,3-fl] quinolizine alkaloids (Entry 1) [13], and Husson and Hashimoto synthesized a derivative of the alkaloid goni-omitine via a Smith indole synthesis (Entry 2) [14]. Henegar and Hunt reported a very convenient synthesis of 2-trifluoromethylindole (Entry 3) [15], in which TMEDA was found to be necessary. Two bis-indoles were prepared in low yield (Entry 4), bnt this approach failed for n = 1 [16], The bridged indole shown in Entry 5 was synthesized following acid-catalyzed cyclization of the initially formed indole [17]. 

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